EP0134946A1 - 3,6-Disubstituted-triazolo[3,4-a]phthalazine derivatives - Google Patents
3,6-Disubstituted-triazolo[3,4-a]phthalazine derivatives Download PDFInfo
- Publication number
- EP0134946A1 EP0134946A1 EP84107562A EP84107562A EP0134946A1 EP 0134946 A1 EP0134946 A1 EP 0134946A1 EP 84107562 A EP84107562 A EP 84107562A EP 84107562 A EP84107562 A EP 84107562A EP 0134946 A1 EP0134946 A1 EP 0134946A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- phenyl
- alkyl
- triazolo
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 29
- -1 3,6- disubstituted-1,2,4-triazolo[3,4-a]phthalazine Chemical class 0.000 claims abstract description 24
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 21
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 14
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 10
- 239000002249 anxiolytic agent Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000003277 amino group Chemical group 0.000 claims abstract description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 9
- 150000001340 alkali metals Chemical class 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- JVJPJKLSGUJUJK-UHFFFAOYSA-N [1,2,4]triazolo[3,4-a]phthalazine Chemical compound C1=CC=C2C=NN3C=NN=C3C2=C1 JVJPJKLSGUJUJK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- XMLOVYHPYJBDBN-UHFFFAOYSA-N 2h-triazolo[4,5-f]phthalazine-4-carbonitrile Chemical compound N#CC1=CC2=CN=NC=C2C2=C1N=NN2 XMLOVYHPYJBDBN-UHFFFAOYSA-N 0.000 claims description 3
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- YSKCSMCLWKOPTC-UHFFFAOYSA-N 6-(2-methoxyethoxymethyl)-3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazine Chemical compound N=1N=C2C3=CC=CC=C3C(COCCOC)=NN2C=1C1=CC=C(OC)C=C1 YSKCSMCLWKOPTC-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Chemical group 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000002130 sulfonic acid ester group Chemical group 0.000 claims 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 230000001131 transforming effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 5
- 230000000049 anti-anxiety effect Effects 0.000 abstract description 4
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000010992 reflux Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 229960003529 diazepam Drugs 0.000 description 8
- 241000700159 Rattus Species 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- SGTXILTYXULEQD-UHFFFAOYSA-N 2H-triazolo[4,5-f]phthalazine Chemical group N1=NC=C2C3=NNN=C3C=CC2=C1 SGTXILTYXULEQD-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 102000004300 GABA-A Receptors Human genes 0.000 description 4
- 108090000839 GABA-A Receptors Proteins 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- IFUAKTVDHXMRSU-UHFFFAOYSA-N 6-(chloromethyl)-3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazine Chemical compound C1=CC(OC)=CC=C1C1=NN=C2N1N=C(CCl)C1=CC=CC=C12 IFUAKTVDHXMRSU-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NYXKBYQZGMXXOW-UHFFFAOYSA-N 2-(4-hydrazinylphthalazin-1-yl)acetonitrile Chemical compound C1=CC=C2C(NN)=NN=C(CC#N)C2=C1 NYXKBYQZGMXXOW-UHFFFAOYSA-N 0.000 description 2
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- IDWSYDRYXUZARN-UHFFFAOYSA-N 3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazine-6-carbonitrile Chemical compound C1=CC(OC)=CC=C1C1=NN=C2N1N=C(C#N)C1=CC=CC=C12 IDWSYDRYXUZARN-UHFFFAOYSA-N 0.000 description 2
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- 150000001450 anions Chemical class 0.000 description 2
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- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
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- 230000003182 bronchodilatating effect Effects 0.000 description 1
- DQGFCLJXYFXXIJ-LFIBNONCSA-N budralazine Chemical compound C1=CC=C2C(N/N=C(C)/C=C(C)C)=NN=CC2=C1 DQGFCLJXYFXXIJ-LFIBNONCSA-N 0.000 description 1
- 229950001730 budralazine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- OMOOCQAIGZYUNY-UHFFFAOYSA-N ethyl phthalazine-6-carboxylate Chemical compound C1=NN=CC2=CC(C(=O)OCC)=CC=C21 OMOOCQAIGZYUNY-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000016290 incoordination Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229950002475 mesilate Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229940071462 oralone Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000005310 triazolidinyl group Chemical group N1(NNCC1)* 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals
Definitions
- the present invention is directed t Q new 3,6-disubstituted-1,2,4-triazolo[3,4-a] phthalazine derivatives, to the process for their preparation and to the pharmaceutical compositions containing them.
- the present invention also encompasses the pharmaceutically-acceptable acid-addition salts of these compounds.
- substituted phenyl is intended to refer to a phenyl group wherein one, two or three hydrogens are replaced by groups each independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halogen, phenyl, hydroxy, amino, mono- and di-(C I -C 4 )alkylamino, (C 2 -C 4 )alkanoylamino and trifluoromethyl.
- alkyl or “alkoxy” per se, as well as the alkyl or alkoxy portions in other substituents containing said moieties, designate straight or branched alkyl or alkoxy groups which contain a number of carbon atoms within the range specified between parenthesis.
- (C 1 -C 4 )alkyl designates a straight or branched alkyl radical which may contain 1, 2, 3 or 4 carbon atoms.
- halogen identified chlorine, bromine, fluorine and iodine atoms.
- saturated 4, 5, 6 or 7 membered heterocyclic rings are: oxazolidinyl isoxazolidinyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, pyrazinidyl, pyrimidinyl pyridazinidyl, morpholinyl, imidazolidinyl, piperazinyl, triazolidinyl, perhydroazepinyl, perhydro- diazepinyl and the like.
- “Pharmaceutically-acceptable acid-addition salts” are the acid addition salts of the compounds of formula I which are not toxic, i.e. whose anion is relatively harmless at dosages compatible with good antianxiety activity in animals so that the pharmacological effects of the compounds of the invention are not impaired by possible side-effects of the anion.
- compositions of formula I are the acid-addition salts of the selected compounds of formula I with mineral acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, or with organic, carboxylic or sulfonic acids, such as lactic, succinic, oxalic, citric- tartaric,
- a preferred group of compounds of the invention includes those compounds of formula I wherein R is phenyl or substituted phenyl, and R 1 is an amine of formula NR 4 R 5 , wherein R 4 and R 5 are as defined above.
- a further group of preferred compounds includes those compounds of formula I wherein R is phenyl and R 1 is NR 4 R 5 wherein R 4 and R 5 represent (C I -C 4 )alkyl groups or (C 1 -C 4 )alkyl groups substituted as defined above or R 4 and R 5 taken together with the adjacent nitrogen atom represent a pyrrolidino, pyrazolidino, piperidino, imidazolidino and morpholino group.
- the compounds of the present invention when tested in vitro in the benzodiazepine receptor binding test, showed to act selectively on the rat brain benzodiazepine receptors displacing 3 H-diazepam from its specific receptors with a considerable potency. Furthermore, the compounds of the present invention showed to be able to displace 3 H-diazepam from its specific brain receptors also when tested in vivo.
- This activity on benzodiazepine receptors is known to reflect, and actually reflects, an antianxiety activity which is detectable in animals by the pharmacological tests usually employed in this field. Said activity is of particular interest in that at the effective doses tested, it is not accompanied by the side effects typically associated to benzodiazepines, such as sedation, motor incoordination, etc.
- a general method for preparing the compounds of the invention is a multistep procedure which comprises the alcoholysis of a cyano-triazolo-phthalazine of the following formula II wherein R, R 2 and R 3 are as defined above, to give the corresponding lower alkyl ester of formula III which is in turn reduced to the corresponding alcohol derivative of formula IV
- the alcoholic function of the triazolo-phthalazine derivative of formula IV is then substituted with a "good leaving group” function, such as a halogen atom or an ester-reactive function to give a triazolo-phthalazine derivative of formula V wherein X is a "good leaving group” as above defined.
- a "good leaving group” function such as a halogen atom or an ester-reactive function
- esters-reactive functions which can be used in this reaction step are sulfonic esters such as the mesilate, tosylate and the like.
- esters-reactive functions are especially preferred when the substrate of the reaction is a 1,2,4-triazolo-phthalazine of the above formula wherein n is equal to 2.
- the alcoholysis of the cyano-triazolo-phthalazine of formula II is conducted by treating a mixture of the compound of formula II in a lower alkanol with hydrogen chloride and hydrolyzing the iminoester hydrochloride so obtained to give the corresponding carboxylic ester, which is recovered by filtration and purified, if necessary or desired, by crystallization.
- the subsequent reduction of the ester derivative of formula III employs an alkali metal boron hydride, such as NaBH 4 or LiBH 4' which are usually used in reducing an ester function to an alcohol one.
- an alkali metal boron hydride such as NaBH 4 or LiBH 4' which are usually used in reducing an ester function to an alcohol one.
- other reducing agents such as LiAlH 4 , A1H 3 , LiAlH(OCH3)3 or NaBH(OCH 3 ) 3 can be used.
- This reaction is carried out in the presence of a suitable polar aprotic inert organic solvent.
- a suitable polar aprotic inert organic solvent Preferably the reaction is conducted at the reflux temperature for some hours, and the reaction course is monitored by means of TLC.
- the hydroxy intermediate of formula IV is then recovered by means of known per se techniques which includes removing the reducing-agent excess, evaporating the solvent under reduced pressure, washing the crude residue with water and drying it.
- the obtained crude intermediate compound of formula IV can be used as such in the subsequent reaction step. However, it may be purified according to usual techniques, such as crystallization.
- the next reaction step, the introduction of the "good leaving group" -X is conducted by known per se techniques which include, when X is a chlorine, bromine or iodine atom, reacting the hydroxy intermediate of formula IV with the suitable hydrohalidic acid, or preferably, with a suitable halogenating agent which is an inorganic acid halogenide, e.g. SOC1 2 , PCl 5 , PC1 3 , POC1 3 and the like, and when X is a sulfonic acid functional group, reacting the intermediate of formula IV with a sulfonic acid activated derivative, preferably a sulfonic acid halogenide.
- a suitable halogenating agent which is an inorganic acid halogenide, e.g. SOC1 2 , PCl 5 , PC1 3 , POC1 3 and the like
- X is a sulfonic acid functional group
- the reaction is conducted in the presence of an aprotic inert organic solvent such as a halogenated aliphatic hydrocarbon, (e.g. methylene chloride) and chloroform; tetrahydrofuran; an aromatic hydrocarbon (e.g. benzene, toluene or xylene).
- an aprotic inert organic solvent such as a halogenated aliphatic hydrocarbon, (e.g. methylene chloride) and chloroform; tetrahydrofuran; an aromatic hydrocarbon (e.g. benzene, toluene or xylene).
- a hydrohalidic acid acceptor preferably a base but more preferably an organic tertiari amine such as a trialkylamine, pyridine, collidine, picoline and the like.
- R 1 is NR4R5and at least one of R and R is a hydroxy(C 1 -C 4 )alkyl group
- R may be transformed into the corresponding halogen (C 1 -C 4 ) alkyl by means of known per se halogenation techniques.
- These halo(C 1 -C 4 )alkyl derivatives of formula I, and preferably the chloro (C 1 -C 4 ) alkyl ones can in turn be reacted with an alkali metal alkoxyde to give the corresponding derivatives of formula I wherein R 4 and/or R represent a (C l -C 4 )alkoxy(C l -C 4 )alkyl group.
- the triazolo-phthalazine derivatives of formula I wherein R 1 represents the group OR 6 can be prepared by reacting the alcohol intermediate of formula IV with an alkali metal hydride to give the corresponding alkali metal alkoxyde which is then reacted with a compound of formula Y-R 6 wherein R 6 is as above and Y represents chloro, bromo or iodo, to give the desired product of formula I.
- nitrile derivatives of formula II can be prepared according to the usual procedures, either by reacting the corresponding haloalkyl or sulfonic ester-triazolo-phthalazine with an alkali metal or copper cyanide or by reacting a 1-phthalazino-hydrazine bearing a group of formula (CH 2 ) n-1 -CN in position 4, with the selected benzoylchloride of formula RCOC1, (wherein R is as defined above).
- the pharmacological properties of the compounds of the present invention were first investigated by submitting some representative members of this class to the benzodiazepine-receptor binding-test in vitro.
- this test which was carried out by following essentially the method described by H. Möhler and T. Okada in Life Sciences, Vol. 20, 2101-2110 (1977), the affinity of the test compounds for the 3 H-diazepam receptor was quantitatively estimated by measuring the inhibition of specific 3 H-diazepam binding to rat brain membranes by the test compounds.
- a constant pulsating shocking current is connected between the grid floor and the tap.
- Each rat is allowed 20 seconds of non-shocked drinking, then cycles of 5 seconds shock-off and*5 seconds shock-on began.
- each lick on the tap is accompanied by shock.
- the number of shocks received by each animal is recorded and minimal effective doses are determined.
- the minimal effective dose is the minimal dose which significantly increases the number of shocks in the treated animals in comparison with controls.
- the MED of the compound of Example 1 in this test is 5 mg/kg, i.p..
- Suitable pharmaceutical compositions contain the novel compounds in admixture or conjunction with organic or inorganic, solid or liquic pharmaceutical excipients and may be employed for enteral or parenteral administration.
- Suitable excipients are substances that do not react with the new compounds, such a: for instance, water, gelatin, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohol, polyalkyleneglycols or other known medicinal excipients.
- the new compounds may be administered by various routes: while the preferred route of administration is the oral one, intramuscular or intraveneous administration can also be employed.
- the substances are compounded in forms such as tablets, dispersible powders, capsules, granules, syrups, elixirs and solutions.
- the active ingredients are embodied into injectable dosage forms.
- compositions are formulated as known in the art.
- the dosage regimen for the compounds of the present invention to be used in an anti-anxiety treatment will depend upon a variety of factors including the particular compound used, the route of administration, and the type of treatment applied for. Good results can be obtained, however, by administering the compounds of the present invention at a daily dosage range comprised between about 0.1 and about 2.0 g preferably administered in divided doses. It is however clear that a daily dosage beyond the above indicated range may also be employed depending on the individual conditions of the subject to be treated. Accordingly, the present invention provides a therapeutic composition comprising from about 25 to about 250 mg of one of the compounds of the invention as the active ingredient together with a pharmaceutically acceptable carrier.
- the active compounds of formula I can be formulated as in the following:
- the following examples describe the preparation of some representative compounds of the invention. Since the exemplified methods are generally applicable simply by selecting the proper substrates according to the suggestions of the present disclosure, the following examples cannot be construed as limiting the scope of the present invention.
- N.M.R. and I.R. spectra are in agreement with the assigned structure.
- the starting 3,4-dihydro-4-oxo-1-phthalazin-acetonitrile is prepared from phthalyl anhydride according to the following method: finely powdered phthalyl anhydride (400 ml), cyanoacetic acid (260 g), anhydrous pyridine (360 ml) are heated at 60°-70°C with stirring for 6 h. The reaction mass is left aside overnight, and then taken up with diluted aqueous hydrochloric acid (1 1) cold stirred for 30 min and filtered. The recovered solid is washed with water and crystallized from acetic acid.
Abstract
Description
- The present invention is directed tQ new 3,6-disubstituted-1,2,4-triazolo[3,4-a] phthalazine derivatives, to the process for their preparation and to the pharmaceutical compositions containing them.
-
- R represents phenyl or substituted phenyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from (C1-C4)alkyl, (Cl-C4)alkoxy, halogen, phenyl, hydroxy, amino, mono- and di-(C1-C4)alkylamino, (C2-C4)alkanoylamino and trifluoromethyl;
- R is selected from an amino group of formula NR 4 R 5 wherein R4 and R5, each independently, represents hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkyl substituted with one or two groups independently selected from hydroxy, (C1-C4)alkoxy, halogen, carboxy and (C1-C4)alkoxycarbonyl; a (CI-C4)alkyl or substituted phenyl-(C1-C4)alkyl group wherein the alkyl portion may be substituted as defined above and the phenyl portion may be substituted with 1, 2 or 3 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxy, halogen, phenyl, hydroxy, amino, mono- and di-(CI-C4)alkylamino, (C1-C4)alkanoylamino, and trifluoromethyl, or R4 and R5 taken together with the adjacent nitrogen atom may represent a saturated 4, 5, 6 or 7-membered heterocyclic ring which may contain a further heteroatom selected from nitrogen, oxygen and sulfur and optionally bear one or two substituents independently selected from (C1-C4)alkyl, phenyl, substituted phenyl, hydroxy, and carbo-(C1-C4)alkoxy, or R1 represents an 6 alkoxy or cycloalkoxy group of formula -OR wherein R6 stands for a (Cl-C6)alkyl group substituted with one or two groups independently selected from hydroxy, amino, mono- or di-(C1-C4)alkylamino, (C1-C4)alkoxy, halogen, oxo, carboxy, and (C1-C4)alkoxycarbonyl, or R is a (C5-C8)cycloalkyl group optionally substituted with one or more hydroxy or (C1-C4)alkoxy groups and
- R 2 and R 3, each independently, represents hydrogen, halogen, (C1-C4)alkyl or (C1-C4)alkoxy.
- Since some of the compounds of the invention possess basic functions (e.g. amines) capable of forming acid-addition salts, the present invention also encompasses the pharmaceutically-acceptable acid-addition salts of these compounds.
- As used herein the term "substituted phenyl" is intended to refer to a phenyl group wherein one, two or three hydrogens are replaced by groups each independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, halogen, phenyl, hydroxy, amino, mono- and di-(CI-C4)alkylamino, (C2-C4)alkanoylamino and trifluoromethyl.
- The terms "alkyl" or "alkoxy" per se, as well as the alkyl or alkoxy portions in other substituents containing said moieties, designate straight or branched alkyl or alkoxy groups which contain a number of carbon atoms within the range specified between parenthesis. Thus, for instance, the term "(C1-C4)alkyl" designates a straight or branched alkyl radical which may contain 1, 2, 3 or 4 carbon atoms.
- The term "halogen" identified chlorine, bromine, fluorine and iodine atoms.
- Representative examples of "saturated 4, 5, 6 or 7 membered heterocyclic rings" as defined in the present invention are: oxazolidinyl isoxazolidinyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, pyrazinidyl, pyrimidinyl pyridazinidyl, morpholinyl, imidazolidinyl, piperazinyl, triazolidinyl, perhydroazepinyl, perhydro- diazepinyl and the like.
- "Pharmaceutically-acceptable acid-addition salts" are the acid addition salts of the compounds of formula I which are not toxic, i.e. whose anion is relatively harmless at dosages compatible with good antianxiety activity in animals so that the pharmacological effects of the compounds of the invention are not impaired by possible side-effects of the anion.
- Representative examples of pharmaceutically-acceptable acid-addition salts are the acid-addition salts of the selected compounds of formula I with mineral acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, or with organic, carboxylic or sulfonic acids, such as lactic, succinic, oxalic, citric- tartaric,
- p.toluenesulfonic, benzenesulfonic, methanesulfonic and the like.
- A preferred group of compounds of the invention includes those compounds of formula I wherein R is phenyl or substituted phenyl, and R1 is an amine of formula NR 4 R 5, wherein R 4 and R5 are as defined above.
- A further group of preferred compounds includes those compounds of formula I wherein R is phenyl and R1 is NR 4 R 5 wherein R4 and R5 represent (CI-C4)alkyl groups or (C1-C4)alkyl groups substituted as defined above or R4 and R5 taken together with the adjacent nitrogen atom represent a pyrrolidino, pyrazolidino, piperidino, imidazolidino and morpholino group.
- The compounds of the present invention when tested in vitro in the benzodiazepine receptor binding test, showed to act selectively on the rat brain benzodiazepine receptors displacing 3H-diazepam from its specific receptors with a considerable potency. Furthermore, the compounds of the present invention showed to be able to displace 3H-diazepam from its specific brain receptors also when tested in vivo.
- This activity on benzodiazepine receptors is known to reflect, and actually reflects, an antianxiety activity which is detectable in animals by the pharmacological tests usually employed in this field. Said activity is of particular interest in that at the effective doses tested, it is not accompanied by the side effects typically associated to benzodiazepines, such as sedation, motor incoordination, etc.
- The s-triazolo [3,4-a] phthalazine ring system was first reported in literature in 1951 when J. Druey and B.H. Ringier in Helvetica Chimica Acta 34, 195, described the synthesis and the physico-chemical characteristics of a series of s-triazolo/3,4-a%phthalazines. Since then, the study of this new ring system developed considerably, leading to the synthesis of several other s-triazolo/3,4-a7phthalazine derivatives, with interest being directed essentially toward their antihypertensive properties (see for instance Chem. Abstracts 80, 37056 a, (1974) and Dissertation Abstr. Intern. B 32, No. 7, 3859 (1972)). This study was further stimulated by the identification of metabolites of hydralazine and budralazine having a triazolo-phthalazine structure (see Arzneimittel - Forsch., 1977, II, 27, 2388-95; Chem. Pharm. Bull. 22, No. 12, 3006-09 (1974) and Chem. Pharm. Bull. 24, No. 11, 2850-58 (1976)). Furthermore several other triazolo [3,4-a] phthalazines have been synthetized up to now, having a different pharmacological activity such as the antiinflammatory activity (see for instance Japanese Patent Application No. 104949/74, Kokai No. 51/032598 (Derwent:Farmdoc 33086 X)), the anticancer activity (see Chem. Abstr. 81, 3864 t, 1974) and the bronchodilating activity (see Chem. Abstr. 80, 37073 d, (1974)). Other s-triazolo [3,4-a] phthalazines are disclosed in Chem. Abstr. 89, 146857n, 1978.
- A general method for preparing the compounds of the invention is a multistep procedure which comprises the alcoholysis of a cyano-triazolo-phthalazine of the following formula II
-
- Examples of "ester-reactive functions" which can be used in this reaction step are sulfonic esters such as the mesilate, tosylate and the like.
- These "ester-reactive functions" are especially preferred when the substrate of the reaction is a 1,2,4-triazolo-phthalazine of the above formula wherein n is equal to 2.
- Finally, the above 1,2,4-triazolo-phthalazine of formula V is reacted with an amine of formula HNR4R5, wherein R4 and R5 are as above defined, or with an alkoxyde or cycloalkoxyde of formula MeOR wherein R6 is as above defined and Me represents an alkali metal atom, to give the desired 1,2,4-triazolo-phthalazine of formula I. More particularly, the alcoholysis of the cyano-triazolo-phthalazine of formula II is conducted by treating a mixture of the compound of formula II in a lower alkanol with hydrogen chloride and hydrolyzing the iminoester hydrochloride so obtained to give the corresponding carboxylic ester, which is recovered by filtration and purified, if necessary or desired, by crystallization.
- The subsequent reduction of the ester derivative of formula III employs an alkali metal boron hydride, such as NaBH4 or LiBH4' which are usually used in reducing an ester function to an alcohol one. Alternatively, other reducing agents such as LiAlH4, A1H3, LiAlH(OCH3)3 or NaBH(OCH3)3 can be used.
- This reaction is carried out in the presence of a suitable polar aprotic inert organic solvent. Preferably the reaction is conducted at the reflux temperature for some hours, and the reaction course is monitored by means of TLC.
- The hydroxy intermediate of formula IV is then recovered by means of known per se techniques which includes removing the reducing-agent excess, evaporating the solvent under reduced pressure, washing the crude residue with water and drying it. The obtained crude intermediate compound of formula IV can be used as such in the subsequent reaction step. However, it may be purified according to usual techniques, such as crystallization.
- The next reaction step, the introduction of the "good leaving group" -X, is conducted by known per se techniques which include, when X is a chlorine, bromine or iodine atom, reacting the hydroxy intermediate of formula IV with the suitable hydrohalidic acid, or preferably, with a suitable halogenating agent which is an inorganic acid halogenide, e.g. SOC12, PCl5, PC13, POC13 and the like, and when X is a sulfonic acid functional group, reacting the intermediate of formula IV with a sulfonic acid activated derivative, preferably a sulfonic acid halogenide.
- The reaction is conducted in the presence of an aprotic inert organic solvent such as a halogenated aliphatic hydrocarbon, (e.g. methylene chloride) and chloroform; tetrahydrofuran; an aromatic hydrocarbon (e.g. benzene, toluene or xylene).
- When preparing sulfonic acid esters of formula V, it is preferred to conduct the reaction in the presence of a hydrohalidic acid acceptor, preferably a base but more preferably an organic tertiari amine such as a trialkylamine, pyridine, collidine, picoline and the like.
- When a compound of formula I is obtained wherein R1 is NR4R5and at least one of R and R is a hydroxy(C1-C4)alkyl group, it may be transformed into the corresponding halogen (C1-C4) alkyl by means of known per se halogenation techniques. These halo(C1-C4)alkyl derivatives of formula I, and preferably the chloro (C1-C4) alkyl ones, can in turn be reacted with an alkali metal alkoxyde to give the corresponding derivatives of formula I wherein R4 and/or R represent a (Cl-C4)alkoxy(Cl-C4)alkyl group.
- Alternatively, the triazolo-phthalazine derivatives of formula I wherein R1 represents the group OR6 can be prepared by reacting the alcohol intermediate of formula IV with an alkali metal hydride to give the corresponding alkali metal alkoxyde which is then reacted with a compound of formula Y-R6 wherein R6 is as above and Y represents chloro, bromo or iodo, to give the desired product of formula I.
- The nitrile derivatives of formula II can be prepared according to the usual procedures, either by reacting the corresponding haloalkyl or sulfonic ester-triazolo-phthalazine with an alkali metal or copper cyanide or by reacting a 1-phthalazino-hydrazine bearing a group of formula (CH2)n-1-CN in position 4, with the selected benzoylchloride of formula RCOC1, (wherein R is as defined above).
- The pharmacological properties of the compounds of the present invention were first investigated by submitting some representative members of this class to the benzodiazepine-receptor binding-test in vitro. In this test, which was carried out by following essentially the method described by H. Möhler and T. Okada in Life Sciences, Vol. 20, 2101-2110 (1977), the affinity of the test compounds for the 3H-diazepam receptor was quantitatively estimated by measuring the inhibition of specific 3H-diazepam binding to rat brain membranes by the test compounds.
- The inhibition is expressed in term of inhibition constant K. which is defined as
Ki = IC50/(1 +C/KD) wherein IC50 is the concentration of test substance required to displace 50 percent of the specific 3H-diazepam binding, C is 3H-diazepam concentration and KD is the affinity constant of 3H-diazepam for its receptor (3.4 x 10-9 M). Compounds with high affinity for the receptor will displace 3H-diazepam at low concentrations (low IC50 values) and are therefore characterized by a low Ki. For instance, in this test the compounds of Examples 1 and 2 exhibited a Ki value of 2 x 10-8 and 1.5 x 10-7, respectively. - The ability of the compounds of the present invention to increase punished responding in animals in a conflict situation, a procedure with high validity for predicting the anxiolytic effect of drugs, was assessed by testing these compounds in rats according to the method described by J.R. Vogel, B. Beer, E.D. Clody in Psychopharmacologia 21, 1-7 (1971) as modified by A.S. Lippa et al., in "Anxiolytics, Industrial Pharmacology", Vol. 3, Futura Publishing, 1979, pages 41-81. Briefly, rats are deprived of water for 48 hours and deprived of food for 20 hours prior to testing. Sixty minutes after administration of the test compound each rat is placed in an especially equipped cage. A glucose solution is available from a tap located in the rear of the cage. A constant pulsating shocking current is connected between the grid floor and the tap. Each rat is allowed 20 seconds of non-shocked drinking, then cycles of 5 seconds shock-off and*5 seconds shock-on began. During the shock-on period each lick on the tap is accompanied by shock. The number of shocks received by each animal is recorded and minimal effective doses are determined.
- The minimal effective dose (MED) is the minimal dose which significantly increases the number of shocks in the treated animals in comparison with controls. The MED of the compound of Example 1 in this test is 5 mg/kg, i.p..
- With the term "use" it is intended to refer to all industrially applicable aspects and acts of said use, including the embodiments of the novel compounds into pharmaceutical compositions.
- Suitable pharmaceutical compositions contain the novel compounds in admixture or conjunction with organic or inorganic, solid or liquic pharmaceutical excipients and may be employed for enteral or parenteral administration. Suitable excipients are substances that do not react with the new compounds, such a: for instance, water, gelatin, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohol, polyalkyleneglycols or other known medicinal excipients. The new compounds may be administered by various routes: while the preferred route of administration is the oral one, intramuscular or intraveneous administration can also be employed. For oral administration, the substances are compounded in forms such as tablets, dispersible powders, capsules, granules, syrups, elixirs and solutions. For intraveneous or intramuscular administration the active ingredients are embodied into injectable dosage forms.
- Such compositions are formulated as known in the art. The dosage regimen for the compounds of the present invention to be used in an anti-anxiety treatment will depend upon a variety of factors including the particular compound used, the route of administration, and the type of treatment applied for. Good results can be obtained, however, by administering the compounds of the present invention at a daily dosage range comprised between about 0.1 and about 2.0 g preferably administered in divided doses. It is however clear that a daily dosage beyond the above indicated range may also be employed depending on the individual conditions of the subject to be treated. Accordingly, the present invention provides a therapeutic composition comprising from about 25 to about 250 mg of one of the compounds of the invention as the active ingredient together with a pharmaceutically acceptable carrier.
- As an example, the active compounds of formula I can be formulated as in the following:
- 6-[(2-Methoxyethoxy)methyl]-3-(4-methoxyphenyl)-1,2,4-triazolo/3,4-a7phthalazine
- A) 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]-phthalazin-6-carbonitrile (26 g) is suspended in cold anhydrous ethanol (550 ml), the cooled mixture is saturated with hydrogen chloride, slowly heated to reflux and kept at the reflux temperature for 2 h. Then, about 200 ml of ethanol are distilled off under reduced pressure and replaced with fresh anhydrous ethanol. The mixture is heated to reflux and kept at this temperature for about 14-16 h under slow hydrogen chloride stream. The solvent is then evaporated under reduced pressure, the residue is taken up with ice-water (200 ml) and the pH of the mixture is adjusted to about 7.5 by adding sodium bicarbonate. After stirring for a few minutes, the reaction mixture is filtered and the collected solid is crystallized from ethanol/chloroform yielding 3-(4-methoxyphenyl)-1,2,4-triazolo/3,4-a7 phthalazin-6-carboxylic acid ethyl ester (27 g). M.p. 180-182°C.
- B) NaBH4 (3.8 g, 0.1 mol) is dissolved in recently distilled diglyme (120 ml) under anhydrous conditions. Anhydrous LiBr (8.7 g, 0.1 mol) is added and the mixture is stirred for 30 min at room temperature. The ester derivative obtained in the foregoing step A (23 g, 0.066 mol) in diglyme (50 ml) is added portionwise. This mixture is then heated to about 80°C for 10 h, then it is cooled, poured into water (800 ml) and the pH of the resulting mixture is brought to about 7 with acetic acid. After stirring for about 20 min, the mixture is filtered and the recovered solid is crystallized from ethanol/chloroform yielding 11.1 g of 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a] phthalazin-6-methanol. M.p. 225-227°C.
- C) A portion of the above obtained 3-(4-methoxyphenyl)-1,2,4-triazolo/3,4-a%phthalazin-6-methanol (10.8 g), anhydrous chloroform (100 ml) and a drop of dimethylformamide are heated at reflux for 6 h, then the solvent is evaporated, the residue is disaggregated with diluted aqueous sodium bicarbonate and filtered. The collected solid is crystallized from ethanol/chloroform yielding 6-(chloromethyl)-3-(4-methoxyphenyl)-1,2,4-triazolo-[3,4-a]phthalazine (10.3 g). M.p. 203-206°C.
- D) Sodium (0.4 g) is dissolved in anhydrous methylcellosolve (60 ml) with stirring and then a portion of 4.5 g of 6-(chloromethyl)-3-(4-methoxyphenyl)-1,2,4-triazolo/3,4-a%phthalazine as obtained above is rapidly added. The mixture is heated at about 120°C for about 5 h, the solvent is evaporated off under reduced pressure, the residue is washed with a small amount of water and crystallized from methanol/water yielding 6-[(2-methoxyethoxy)methyl]-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazine (3 g). M.p. 129-131°C.
N.M.R. and I.R. spectra are in agreement with the' assigned structure. - 3-(4-Methoxyphenyl)-6-[(1-pyrrolidinyl)methyl]--1,2,4-triazolo[3,4-a]phthalazine
- 6-(Chloromethyl)-3-(4-methoxyphenyl)-1,2,4-triazolo-[3,4-a]phthalazine (3 g) and pyrrolidine (30 ml) are heated at 100°C for 8 h in autoclave. The amine excess is removed, the residue is washed with a small amount of water and crystallized from ethyl acetate, yielding 3-(4-methoxyphenyl)-6-[(1-pyrrolidinyl)methy]--1,2,4-triazolo/3,4-a7phthalazine (1.7 g). M.p. 184-186°C.
- N,N-Bis(2-methoxyethyl)-3-(4-methoxyphenyl)-1,2,4-triazo-10[3,4-a]phthalazin-6-methanamine hydrochloride
- A mixture of 6-(chloromethyl)-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazine (see Example 1, step C; 4 g) and bis-N-(2-methoxyethyl)amine (40 ml) is heated to about 140°C for 30 h. The solvent is then evaporated under reduced pressure, the residue is disaggregated in water and extracted with methylene chloride. The separated organic phas. is distilled under reduced pressure and the obtained oily residue is purified by silicagel column chromatography eluting with 0.5% methanol in chloroform. The solvent of the fractions containing the desired product (head fractions) is distilled under reduced pressure giving an oily residue which is salified with hydrogen chloride to give N,N-Bis(2-methoxyethyl)-3-(4-methoxyphenyl)-1,2,4-triazo-10[3,4-a]phthalazin-6-methanamine hydrochloride (3.6 g) which crystallizes from ethanol/ethyl ether. M.p. 204-206°C.
- N.M.R. and I.R. spectra are in agreement with the assigned structure.
- N,N-Bis-(2-methoxyethyl)-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]ghthalazin-6-ethaneamine hydrochloride
- A) 3-(4-Methoxyphenyl)-1,2,4-triazolo/3,4-a7-phthalazin-6-acetonitrile (0.65 g) is suspended in absolute ethanol (10 ml) and the cooled mixture is saturated with hydrogen chloride, heated at reflux for about 8 h and concentrated to dryness. The residue is taken up with water (5 ml) and brought to pH 7.5 with sodium bicarbonate. The mixture is filtered and the recovered solid is crystallized with ethanol/chloroform yielding 3-(4-methoxyphenyl)-1,2,4-triazolo/3,4-afphthalazin-6-acetic acid ethyl ester (0.55 g). M.p. 201-202°C.
- B) A portion of the above compound (0.3 g) is added to a solution of LiBH4 (0.05 g) in anhydrous diglyme (5 ml) and the mixture is heated at 90°C for 8 h. Then it is cooled to room temperature, acidified with acetic acid and concentrated to dryness. The residue is washed with water and crystallized from methylcellosolve, yielding 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazin-6-ethan-2-ol (0.17 g). M.p. 240-243°C.
- C) 3-(4-Methoxyphenyl)-1,2,4-triazolo/3,4-a7-phthalazin-6-acetic acid ethyl ester (0.10 g) and triethylamine (0.4 g) are dissolved in methylene chloride (15 ml) and methanesulfonyl chloride (0.4 g) is added thereto. The reaction mixture is heated (water bath) for 1.5 h and then poured into ice-water (150 ml) and stirred until when an oily product separates from the mixture. This oily product solidifies and is then recovered by filtration, washed with cold diluted hydrochloric acid, then with diluted aqueous sodium hydroxide and finally with water up to neutrality. This residue is crystallized from methanol yielding 0.7 g of 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]-phthalazin-6-ethan-2-ol, methanesulfonate.
- D) Essentially following the procedure of Example 3 but substituting the above obtained 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazin-6-ethan-2-ol, methanesulfonate for 6-(chlorometil)-3-(4-methoxyphenyl)-1,2,4-triazolo/3,4-a%phthalazine, the product of the title, (i.e. N,N-Bis-(2-methoxyethyl)-3-(4-methoxyphenyl)-1,2,4-triazolol3,4-a%- phthalazin-6-ethaneamine hydrochloride) is obtained (yield 43%).
-
- Preparation of 3-(4-methoxyphenyl)-1,2,4-triazolo-[3,4-a]phthalazin-6-carbonitrile
- A) 50% NaH (6 g) is suspended in 300 ml of anhydrous dimethylformamide in a 1 1 flask and stirred for about 10 min, then, after cooling to 10°C, ethanethiol (9 ml) dissolved in anhydrous dimethylformamide (60 ml) is added thereto. The reaction mixture is stirred for about 30 min and then 38.6 g of 6-chloro-3-(4-methoxyphenyl)triazolo/3,4-a7-phthalazine is added portionwise. The resulting mixture is stirred for about 5 h at 50°C and cooled, a solid is collected by filtration, giving 30 g of 6-ethylthio-3-(4-methoxyphenyl)-1,2,4-triazolo-[3,4-a]phthalazine. By evaporating the solvent of the mother liquors, a solid is obtained which is taken up with water and collected by filtration giving a further crop of 7 g of 6-ethylthio-3-(4-methoxyphenyl)-1,2,4-triazolo/3,4-alphthalazine. These two portions are pooled and crystallized from a mixture methanol/ethyl ether, 1:1 giving 36 g of pure product. M.p. 176-178°C.
- B) 35.5 g of the above product are suspended in 450 ml of glacial acetic acid and 36% (v/v) hydrogen peroxide (37 ml). After 5 days of reaction, with stirring from time to time, the reaction mixture is poured into water (1500 ml) and the precipitate which forms is recovered by filtration yielding 3-(4-methoxyphenyl)-6-(e hylsulfonyl)-1,2,4-triazolo[
3 ,4-a]phthalazine (35 g). M.p. 210-213°C. - C) This product is in turn dissolved in hot dimethylformamide (400 ml), the resulting solution is cooled to about 30°C and potassium cianyde (11.5 g) is added thereto. This mixture is stirred at room temperature for about 5 h and then the solvent is distilled under reduced pressure. The residue is taken up with a small amount of water and crystallized from ethanol/chloroform yielding 26 g of 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]ph- thalazin-6-carbonitrile. M.p. 230-232°C.
- 6-Chloro-3-(4-methoxyphenyl)-triazolo[3,4-a]-phthalazine is described in European Patent Application No. 83100232.4.
- Preparation of 3-(4-methoxyphenyl)-1,2,4-triazolo-[3,4-a]phthalazin-6-acetonitrile
- A) 3,4-dihydro-4-oxo-l-phthalazin-acetonitrile (126 g) is suspended in anhydrous pyridine (1300 ml) under anhydrous conditions. P2s5 (230 g) is added portionwise to this suspension at room temperature and with stirring, then the mixture is slowly heated to reflux temperature and kept at this temperature for about 2 h. Pyridine is then evaporated under reduced pressure and the residue is poured into water (3 1). The solid which separates is recovered by filtration, thoroughly washed first with water and then with cold diluted aqueous ammonia. The recovered solid is oven-dried, yielding 4-mercapto-1-phthalazin-acetonitrile (110 g).
- B) The above product (1 g) is added to a solution of hydrazine hydrate (1 g) in dioxane (15 ml) at 50°C. The mixture is heated at the reflux for 1 h and activated carbon is added. The solution which residuates after filtering the reaction mixture is concentrated to dryness, the obtained solid mass is taken up with water, recovered by filtration and crystallized from ethanol/chloroform yielding 0.91 g of 4-hydrazino-1-phthalazin-acetonitrile. M.p. 187-190°C.
- C) A mixture of 4-hydrazino-1-phthalazin-acetonitrile (0.7 g), triethylamine (0.4 g), p-methoxybenzoyl- chloride (0.68 g), dioxane (10 ml), is heated at reflux for 5 h, then it is cooled, the solvent is evaporated under reduced pressure, the residue is taken up with water, recovered by filtration and crystallized from ethanol/chloroform, yielding 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]ph- thalazin-6-acetonitrile. M.p. 252-254°C.
- The starting 3,4-dihydro-4-oxo-1-phthalazin-acetonitrile is prepared from phthalyl anhydride according to the following method: finely powdered phthalyl anhydride (400 ml), cyanoacetic acid (260 g), anhydrous pyridine (360 ml) are heated at 60°-70°C with stirring for 6 h. The reaction mass is left aside overnight, and then taken up with diluted aqueous hydrochloric acid (1 1) cold stirred for 30 min and filtered. The recovered solid is washed with water and crystallized from acetic acid. Then it is suspended in ethanol (1.4 1), hydrazine hydrate (60 ml) is slowly added and the resulting clear solution is heated at reflux for about 4 h. Then, the reaction mixture is allowed to cool to room temperature and the solid precipitate which forms is separated and washed with methanol, yielding 160 g of 3,4-dihydro-4-oxo-l-ph- thalazin-acetonitrile. M.p.238-240°C (from ethanol/chloroform).
Claims (10)
- CLAIMS FOR THE CONTRACTING STATES: BE CH DE FR GB IT LU NL SE
- 1. A 1,2,4-triazolo[3,4-a]phthalazine of formulaR represents phenyl or substituted phenyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from (C1-C4)alkyl, (CI-C4)alkoxy, halogen, phenyl, hydroxy, amino, mono- and di-(C1-C4)alkylamino, (C2-C4)alkanoylamino and trifluoromethyl;R is selected from an amino group of formula NR4R5 wherein R 4 and R5, each independently, represents hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkyl substituted with one or two groups independently selected from hydroxy, (C1-C4)alkoxy, halogen, carboxy and (C1-C4)alkoxycarbonyl; a (C1-C4)alkyl or substituted phenyl-(C1-C4)alkyl group wherein the alkyl portion may be substituted as defined above and the phenyl portion may be substituted with 1, 2 or 3 substituents selected from (C 1-C 4)alkyl, (C1-C4)alkoxy, halogen, phenyl, hydroxy, amino, mono- and di-(C1-C4)alkylamino, (C1-C4)alkanoylamino, and trifluoromethyl, or R4 and R5 taken together with the adjacent nitrogen atom may represent a saturated 4, 5, 6 or 7-membered heterocyclic ring which may contain a further heteroatom selected from nitrogen, oxygen and sulfur and optionally bear one or two substituents independently selected from (C1-C4)alkyl, phenyl, substituted phenyl, hydroxy, and carbo-(C1-C4)alkoxy, or R 1 represents an alkoxy or cycloalkoxy group of formula -OR6 wherein R6 stands for a (C1-C6)alkyl group substituted with one or two groups independently selected from hydroxy, amino, mono- or di-(C1-C4)alkylamino, (C1-C4)alkoxy, halogen, oxo, carboxy, and (C1-C4)alkoxycarbonyl, or R is a (C5-C8)cycloalkyl group optionally substituted with one or more hydroxy or (Cl-C4)alkoxy groups and 3R2 and R3, each independently, represents hydrogen, halogen, (Cl-C4)alkyl or (Cl-C4)alkoxy, and the pharmaceutically acceptable acid-addition salt thereof.
- 2. A compound according to claim 1 wherein R is phenyl or substituted phenyl, and R1 is an amine of formula NR 4 R 5, wherein R4 and R5 are as defined above.
- 3. A compound according to claim 1 wherein R is phenyl and R 1 is NR4R5wherein R4 and R5 represent (C1-C4)alkyl groups or (C1-C4)alkyl groups substituted as defined above or R4 and R5 taken together with the adjacent nitrogen atom represent a pyrrolidino, pyrazolidino, piperidino, imidazolidino and morpholino group.
- 4. A compound according to claim 1 which is 6-[(2-methoxyethoxy)methyl]-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazine.
- 5. A process for preparing a compound of claim 1 which comprises reacting a 1,2,4-triazolo[3,4-a]phthalazine intermediate of formula V
- 6. A process for preparing a compound of claim 1 which comprises:a) submitting a cyano-triazolo-phthalazine of formula IIc) transforming this alcohol derivative of formula IV into a 1,2,4-triazolo-phthalazine intermediate of formula Vd) reacting this 1,2,4-triazolo[3,4-a]phthalazine intermediate with an amine of formula HNR 4 R 5 or with an alkali metal alkoxyde or cycloalkoxyde of formula MeOR6, wherein R4, R5 and R are as defined in claim 1 and Me represents an alkali metal.
- 7. An intermediate compound in the process for preparing a compound of claim 1 which has one of the following formulas
- 8. A compound of claim 1 for use as an anti-anxiety agent.
- 9. A pharmaceutical formulation which comprises a compound of claim 1 as the active ingredient in admixture with a pharmaceutically acceptable vehicle.
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EP0029130A1 (en) * | 1979-10-29 | 1981-05-27 | The Dow Chemical Company | 3,6,7,8-Substituted-s-triazolo(4,3-b)-pyridazines, their preparation and compositions comprising them |
EP0085840A1 (en) * | 1982-01-18 | 1983-08-17 | Gruppo Lepetit S.P.A. | New 6-substituted-s-triazolo(3,4-a)phthalazine derivatives |
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GB629177A (en) * | 1945-12-21 | 1949-09-14 | Ciba Ltd | Manufacture of new hydrazine compounds and derivatives thereof |
US2484029A (en) * | 1945-12-21 | 1949-10-11 | Ciba Pharm Prod Inc | Hydrazine derivatives of pyridazine compounds |
US3711481A (en) * | 1970-04-24 | 1973-01-16 | G Hardtmann | 6-aryl-imidazo(2,1-a)phthalazines |
US3694442A (en) * | 1970-07-28 | 1972-09-26 | William J Houlihan | SUBSTITUTED TETRAHYDRO-1H-PYRAZOLO{8 1,2-b{9 PHTHALAZINES |
US3704300A (en) * | 1971-04-09 | 1972-11-28 | Sandoz Ag | Imidazo(2,1-a)phthalazines |
JPS603080B2 (en) * | 1976-08-10 | 1985-01-25 | 三菱化学株式会社 | S-triazolo[3,4-α][5,6,7,8]tetrahydrophthalazines |
US4391807A (en) * | 1982-07-12 | 1983-07-05 | The Dow Chemical Company | 6-Substituted tetrahydroimidazo[2,1-a]phthalazines and use as bronchodilators |
US4485106A (en) * | 1982-07-12 | 1984-11-27 | The Dow Chemical Company | Substituted tetrahydrotetrazolo[5,1-a]phthalazines |
US4487930A (en) * | 1982-09-07 | 1984-12-11 | The Dow Chemical Company | 6-[(Cyclic amino)alkylamino]-tetrahydrotriazolo[3,4-a]phthalazines |
-
1983
- 1983-07-12 IT IT22014/83A patent/IT1194310B/en active
-
1984
- 1984-06-29 EP EP84107562A patent/EP0134946B1/en not_active Expired
- 1984-06-29 AT AT84107562T patent/ATE28874T1/en not_active IP Right Cessation
- 1984-06-29 DE DE8484107562T patent/DE3465309D1/en not_active Expired
- 1984-07-03 AU AU30224/84A patent/AU560726B2/en not_active Ceased
- 1984-07-06 DK DK331884A patent/DK164704C/en not_active IP Right Cessation
- 1984-07-10 JP JP59141573A patent/JPS6056982A/en active Granted
- 1984-07-11 US US06/629,658 patent/US4783461A/en not_active Expired - Fee Related
- 1984-07-11 CA CA000458575A patent/CA1234114A/en not_active Expired
Patent Citations (2)
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EP0029130A1 (en) * | 1979-10-29 | 1981-05-27 | The Dow Chemical Company | 3,6,7,8-Substituted-s-triazolo(4,3-b)-pyridazines, their preparation and compositions comprising them |
EP0085840A1 (en) * | 1982-01-18 | 1983-08-17 | Gruppo Lepetit S.P.A. | New 6-substituted-s-triazolo(3,4-a)phthalazine derivatives |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
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US6465462B1 (en) | 1996-07-25 | 2002-10-15 | Merck Sharp & Dohme Ltd. | Substituted triazolo pyridazine derivatives as inverse agonists of the GABAAα5 receptor subtype |
EA002436B1 (en) * | 1996-07-25 | 2002-04-25 | Мерк Шарп Энд Домэ Лимитед | Substituted triazolo-pyridazine derivatives as ligands for gaba receptors |
US6255305B1 (en) | 1996-07-25 | 2001-07-03 | Merck Sharp & Dohme Limited | Substituted triazolo-pyridazine derivatives as ligands for GABA receptors |
WO1998004560A1 (en) * | 1996-07-25 | 1998-02-05 | Merck Sharp & Dohme Limited | SUBSTITUTED TRIAZOLO PYRIDAZINE DERIVATIVES AS INVERSE AGONISTS OF THE GABAAα5 RECEPTOR SUBTYPE |
US6200975B1 (en) | 1997-05-08 | 2001-03-13 | Merck Sharp & Dohme Limited | Substituted 1,2,4-triazolo[3,4-a]phthalazine derivatives as GABA alpha 5 ligands |
US6310203B1 (en) | 1997-05-08 | 2001-10-30 | Merck Sharpe & Dohme Limited | Precursor compounds to substituted 1,2,4-triazolo[3,4,-a]phathalazine GABA alpha 5 ligands |
WO1999006407A1 (en) * | 1997-07-29 | 1999-02-11 | Merck Sharp & Dohme Limited | THERAPEUTICALLY ACTIVE 1,2,4-TRIAZOLO(4.,3-b) PYRIDAZINE DERIVATIVES AS LIGANDS FOR GABA RECEPTORS |
US6313125B1 (en) | 1997-07-29 | 2001-11-06 | Merck Sharp & Dohme Ltd. | Therapeutically active 1,2,4-triazolo[4.,3-B] pyridazine derivatives as ligands for GABA receptors |
US6174886B1 (en) | 1997-11-13 | 2001-01-16 | Merck Sharp & Dohme Ltd. | Antipsychotic use of triazolo-pyridazine derivatives |
US6046196A (en) * | 1997-12-18 | 2000-04-04 | Merck Sharp & Dohme Ltd. | Antispastic use of triazolo-pyridazine derivatives |
US6110915A (en) * | 1997-12-18 | 2000-08-29 | Merck & Co., Inc. | Antiemetic use of triazolo-pyridazine derivatives |
US6107296A (en) * | 1997-12-18 | 2000-08-22 | Merck Sharp & Dohme, Ltd. | Neuroprotective use of triazolo-pyridazine derivatives |
US6063783A (en) * | 1997-12-18 | 2000-05-16 | Merck Sharp & Dohme Ltd. | Analgesic use of triazolo-pyridazine derivatives |
US6303597B1 (en) | 1998-01-14 | 2001-10-16 | Merck Sharp & Dohme Limited | Triazolo-pyridazine derivatives as ligands for GABA receptors |
WO1999036423A1 (en) * | 1998-01-14 | 1999-07-22 | Merck Sharp & Dohme Limited | Triazolo-pyridazine derivatives as ligands for gaba receptors |
US6579875B1 (en) | 1998-01-21 | 2003-06-17 | Merck Sharp & Dohme Limited | Triazolo-pyridazine derivatives as ligands for GABA receptors |
US6355798B1 (en) | 1998-01-21 | 2002-03-12 | Merck Sharp & Dohme Ltd. | Triazolo-pyridazine derivatives as ligands for GABA receptors |
US6319924B1 (en) | 1998-01-21 | 2001-11-20 | Merck Sharp & Dohme Ltd. | Triazolo-pyridazine derivatives as ligands for GABA receptors |
US6303605B1 (en) | 1998-01-21 | 2001-10-16 | Merck Sharp & Dohme Ltd. | Triazolo-pyridazine derivatives as ligands for GABA receptors |
US6699859B1 (en) | 1998-01-21 | 2004-03-02 | Merck Sharp & Dohme Ltd. | Triazolo-pyridazine derivatives as ligands for GABA receptors |
US6828322B2 (en) | 1998-01-21 | 2004-12-07 | Merck Sharp & Dohme Ltd. | Triazolo-pyridazine derivatives as ligands for GABA receptors |
US6291460B1 (en) | 1998-01-22 | 2001-09-18 | Merck Sharp & Dohme Limited | Triazolo-pyridazine derivatives as ligands for GABA receptors |
US6399608B1 (en) | 1998-01-23 | 2002-06-04 | Merck Sharp & Dohme Ltd. | Combination of a GABA-A α 2/3 agonist and a selective serotonin reuptake inhibitor |
US6448249B1 (en) | 1998-02-25 | 2002-09-10 | Merck Sharp & Dohme Ltd. | Substituted 1,2,4-triazolo[3,4-A]phthalazine derivatives as GABAα5 ligands |
US6534505B2 (en) | 1998-11-12 | 2003-03-18 | Merck & Co., Inc. | Therapeutic polymorphs of a GABA-A alpha-5 inverse agonist and pamoate formulations of the same |
US6613766B1 (en) | 1998-11-12 | 2003-09-02 | Merck Sharp & Dohme Ltd. | Pentaaza-cyclopental[a]naphthalene derivatives as ligands for GABAa α5 receptors |
US6900209B2 (en) | 2000-11-23 | 2005-05-31 | Merck Sharp & Dohme Ltd. | Nitrogen substituted 1,2,4-triazolo[3,4-a]phthalazine derivatives for enhancing cognition |
US8269037B2 (en) | 2009-01-29 | 2012-09-18 | Basf Se | Absorption medium for removing acid gases which comprises amino acid and acid promoter |
Also Published As
Publication number | Publication date |
---|---|
JPH051267B2 (en) | 1993-01-07 |
DK331884A (en) | 1985-01-13 |
EP0134946B1 (en) | 1987-08-12 |
DK164704B (en) | 1992-08-03 |
CA1234114A (en) | 1988-03-15 |
IT8322014A0 (en) | 1983-07-12 |
DK164704C (en) | 1992-12-21 |
DK331884D0 (en) | 1984-07-06 |
JPS6056982A (en) | 1985-04-02 |
IT1194310B (en) | 1988-09-14 |
US4783461A (en) | 1988-11-08 |
ATE28874T1 (en) | 1987-08-15 |
AU560726B2 (en) | 1987-04-16 |
DE3465309D1 (en) | 1987-09-17 |
AU3022484A (en) | 1985-01-17 |
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